The interferon system operates as a defense mechanism in infected cells, resulting in inhibition of virus replication. Many viruses display countermeasures against the interferon response that allow them to replicate. Positive-stranded RNA viruses like hepatitis C virus and poliovirus possess such mechanisms and so do many negative-stranded RNA and DNA viruses. This proposal outlines a series of experiments designed to investigate the mechanisms employed by dengue virus to antagonize the antiviral effects of interferon. Reporter systems have been developed and applied to identify dengue virus proteins with the ability to block interferon signaling, or to enhance viral replication in the presence of interferon. Functional assays and mutational analysis will delineate the involvement of the dengue interferon antagonists identified. Dr. Munoz plans to engineer dengue viruses expressing a defective interferon antagonist, and expects that their capacity to replicate will be hindered in interferon-competent hosts. Thus, his findings may have therapeutic implications. The identification of dengue virus-encoded interferon antagonists will probably point to homologues in other insect-borne flaviviruses of medical or bio-terrorism importance. Therefore, his studies may uncover mechanisms of pathogenesis present in important viruses.